JP2001247595A - 8a-oxahomoerythromycin derivative, method of producing the same, synthetic intermediate and medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new 15-membered ring 8a-oxahomoerythromycin derivative which has two ester bonds in the ring, to provide a method of producing the same, to provide a synthetic intermediate, and to provide a medicinal composition containing the same. SOLUTION: This 8a-oxahomoerythromycin derivative represented by the formula (I), a salt thereof, a prodrug thereof, or hydrates thereof, and the method of synthesizing the 8a-oxahomoerythromycin derivative, characterized by applying a transesterification reaction to a new synthetic intermediate to expand the ring, and a medicinal composition containing the 8a- oxahomoerythromycin derivative, are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to erythromycin derivatives which are macrolide antibiotics. More specifically, the present invention relates to an erythromycin derivative which is a novel dilactone type macrolide having two ester bonds in the ring.

[0002]

BACKGROUND OF THE INVENTION Erythromycin is the first macrolide antibiotic isolated from the culture of Streptomyces erythreusk isolated from soil in the Philippines in 1952 and is resistant to Gram-positive bacteria. It showed antimicrobial activity, especially the emergence of penicillin-resistant staphylococci at the time and the penicillin shock, which widened the use of erythromycin.

[0003] Erythromycin is structurally a 14-membered ring macrolide having one ester bond in the ring.
The erythromycin derivative of the present invention is a novel 15-membered ring macrolide having two ester bonds in the ring (hereinafter, the erythromycin derivative of the present invention is referred to as 8a-oxahomoerythromycin derivative). The compounds of the present invention have not been synthesized by conventional methods used for modifying the structure of erythromycin because their synthesis is extremely difficult.

According to the method of the present invention, an 8a-oxahomoerythromycin derivative can be synthesized simply and with high yield by partially reconstructing the nucleus of erythromycin. Furthermore, it was found that the 8a-oxahomoerythromycin derivative had an antibacterial activity equivalent to that of erythromycin.

In Japanese Patent Application Laid-Open No. 47-8089, starting from erythromycin, a compound different from the compound of the formula (II) of the present invention but similar to 8,9-seco-8-oxoerythromycin A-9- Oic acid 6,9-lactone is obtained as a by-product (Publication 4, Example 7). However, the compound disclosed in JP-A-47-8089 is not the target compound and the yield is not described.

[Means for Solving the Problems]

A first aspect of the present invention is an 8a-oxahomoerythromycin derivative of the formula (I), whose synthesis has been extremely difficult from the conventional methods used for modifying the structure of erythromycin:

Embedded image Wherein R ¹ ＲR ² ＯＨOH or R ¹ and R ² together

Embedded image (Where R ⁵ = (CH ₂ ) n-aryl, and n is 1-6
R ³ ＨH, an acyl group, or an optionally substituted lower alkyl group, or 3
R ⁴ ＨH, an acyl group, or

Embedded image Or forms a CＯO with the ring carbon at position 3 (shown in dotted lines); Z ¹ is a protecting group for H or a hydroxy group; Z ² is a protecting group for Me or an amino group is there)
Or a salt, prodrug, or hydrate thereof.

A second aspect of the present invention is a compound of the formula (I ') further defining the configuration of the formula (I):

Embedded image Or a salt, prodrug, or hydrate thereof.

The third step of the present invention is a step of the process for producing the compound of the formula (I) of the present invention, wherein a transesterification reaction is applied to increase the number of ring members.

Embedded image (Wherein, R ⁶ is H, an acyl group or a sulfonyl group, Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group);
And a method for producing the compound represented by the formula:

A fourth aspect of the present invention is a reaction formula B, which is a part of the method for producing the compound of the formula (I) of the present invention:

Embedded image Wherein R ⁶ is H or an acyl group or a sulfonyl group, and Z ¹ is H or a protecting group for a hydroxy group;
Z ² is a protecting group for Me or an amino group);
It is intended to provide a process for producing the compound represented by (III).

A fifth aspect of the present invention is a reaction formula C which is a main part of the process for producing the compound of the formula (I) of the present invention:

Embedded image (Wherein R ⁶ is H, an acyl group or a sulfonyl group; Z ¹ is a protecting group for H or a hydroxy group; Z ²
Is a protecting group for Me or an amino group),
And a method for producing the compound represented by the formula:

The sixth to eighth inventions are represented by the formula (II), which is a synthetic intermediate of the compound of the formula (I) of the invention.

Embedded image (Wherein Z ¹ is H or a protecting group for a hydroxy group;
Z ² is a protecting group for Me or an amino group), a compound represented by the formula (III):

Embedded image (Wherein, R ₆ is H, an acyl group or a sulfonyl group, Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group) and a compound represented by the formula (V):

Embedded image (Wherein Z ¹ is H or a protecting group for a hydroxy group;
Z ² is a protecting group for Me or an amino group).

A ninth aspect of the present invention is a pharmaceutical composition containing the above 8a-oxahomoerythromycin derivative.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The starting material of the present invention has the following formula
(3):

Embedded image (Z ₁ = Z ₂ = H) is described in Recueil, Journ
al of the Royal Netherlands Chemical Society, 94 (1
1), 236-238 (1975).

Examples of the “acyl group” for R ³ include:
Carbamoyl, thiocarbamoyl, acetyl, p-methoxyphenylacetyl and the like. Examples of the “lower alkyl group” for R ³ include methyl, ethyl, propyl, butyl and the like.

Examples of the “acyl group” for R ⁴ include:
Optionally substituted phenylacetyl such as nitro, methoxy, phenyl, methylphenyl, chloro, for example p-, m- or o-nitrophenylacetyl, p
-, M- or o-methoxyphenylacetyl, biphenylacetyl, α-methylbiphenylacetyl, p-,
and m- or o-chlorophenylacetyl.

R ⁵ "aryl" includes:
Phenyl, a monocyclic or fused heterocyclic compound containing 1 to 3 nitrogen atoms, for example, pyridyl, quinolyl, isoquinolyl, quinoxalyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, a monocyclic heterocyclic compound containing one sulfur atom, For example, thienyl, monocyclic heterocyclic compounds containing one oxygen atom, for example, furyl and the like. n is 1-6, preferably 1-4.

Examples of the "acyl group" for R ⁶ include the same as the aforementioned "acyl group" for R ³ .

Representative examples of the hydroxy-protecting group (Z ¹ ) and a method for removing the same are described, for example, in “Shin Jikken Kagaku Koza”, Vol. 14, pp. 2497-2516. Acetals such as methyl ether (eliminated with boron trichloride), allyl ether (isomerized to propenyl ether and then acid-catalyzed hydrolysis), benzyl ether (catalytic hydrogenolysis), and triarylmethyl ether (eliminated with acetic acid) As the type, such as tetrahydropyranyl ether (eliminated by acid-catalyzed hydrolysis), etc., as the ester type, acetate (eliminated by base hydrolysis), formate
(Eliminated with KHCO ₃ —H ₂ O—CH ₃ OH) or trifluoroacetic acid (eliminated with KHCO ₃ —CH ₃ OH), chloroacetic acid ester (eliminated with C ₆ H ₅ N—C ₂ H ₅ OH) , methoxy and phenoxy substituted acetic acid esters, such as acetate (removable by NH ₃ -CH ₃ OH), such as benzoic acid esters and p- nitrobenzoic acid ester (removable by base hydrolysis), ethoxycarbonyl (KOH-CH ₃ desorption with OH), leaving at allyloxycarbonyl (Ni (CO) 4, Me 2 CH 2 CH 2 Me 2), phenylcarbamoyl (CH ₃ ONa- thermal CH ₃ OH
With benzylthiocarbonyl (H ₂ O ₂ —CH ₃ CO ₂
Non-carboxylic acid esters, such as carbonic acid esters such as H (eliminated with H), nitric acid esters (eliminated with Na ₂ S, etc.), and sulfonic acid esters (Na-Hg-CH ₃ OH) are used.

Representative examples of the amino-protecting group (Z ² ) and a method for removing the same are described, for example, in “Shin Jikken Kagaku Koza”, Vol. 14, pp. 2555-2569. Examples include lower alkanoyl groups such as formyl (eliminated with HCl / CH ₃ OH), acetyl (eliminated with acid or alkali), halo lower alkanoyl groups such as 2-chloropropionyl (eliminated with acid or alkali), benzoyl Arylcarbonyl groups such as (eliminated with acid or alkali), phenylpropionyl (eliminated with acid or alkali)
Aryl lower alkanoyl groups, such as methoxycarbonyl, ethoxycarbonyl,
Lower alkoxycarbonyl groups such as butoxycarbonyl (eliminated with HBr or HCl / AcOH), benzyloxycarbonyl (H ₂ / Pd, HI or HBr or HCl)
Aryl lower alkyloxycarbonyl groups such as 2- (p-biphenyl) isopropoxycarbonyl (eliminated with AcOH / HCOOH, trifluoroacetic acid, etc.); benzyl (H
Aryl lower alkyl groups such as ₂ / Pd and Na / NH ₃ ) and trityl (eliminated with H ₂ / Pd), and azomethine-type benzylidene (H ₂ / Pd with HCl). And the like.

In the above groups, "lower" is a group having 6 or less carbon atoms, and "aryl" is a group containing 1 to 3 benzene nuclei. The nature of the "hydroxy protecting group" and "amino protecting group" as described above is not important, as they should be eliminated last.

The term “substituted” in the case of “optionally substituted” means having a substituent that does not adversely affect the reaction, such a lower alkyl or lower alkoxy. Alkenyl, lower alkynyl, phenyl, halogen, hydroxy, nitro and the like.

Salts include salts with acids and salts with bases. Physiologically acceptable salts are salts that do not exhibit significant toxicity at the dosage and do not have the physical or chemical properties that make administration difficult. Among such salts, salts with acids include salts with inorganic acids (mineral acids) such as hydrochloric acid, sulfuric acid, and phosphoric acid, and carboxylic acids such as acetic acid, tartaric acid, citric acid, succinic acid, and fumaric acid. Salts with organic acids such as sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and toluenesulfonic acid are included. Examples of the salt with a base include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, polyvalent metal salts such as aluminum salts and manganese salts, trimethylamine salts, triethylamine salts, and cyclohexyl. Organic amine salts such as amine salts, ethanolamine salts, diethanolamine salts, tromethamine salts, morpholine salts, piperidine salts, procaine salts and caffeine salts are included. If there are a large number of carboxy groups, any number of them can be salts.

A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. is there. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterda.
m 1985.

Since the compound of the present invention has a hydroxyl group, examples thereof include prodrugs such as acyl derivatives produced by reacting with a suitable acyl halide or a suitable acid anhydride. Particularly preferred acyl as prodrugs, -OCOC ₂ H _5, -OCO
(t-Bu), - OCOC 15 H 31, -OCO (m-COO
_{Na-Ph), - OCOCH 2} CH 2 COONa, -OC
_{OCH (NH 2) CH 3,} -OCOCH 2 N (CH 3) 2 and the like.

The compound of the present invention may have an amino group, and examples thereof include prodrugs such as amide derivatives produced by reacting with a suitable acid halide or a suitable mixed acid anhydride. Particularly preferred amides as prodrugs, -NHCO (CH _{2) 20} C
_{H 3, -NHCOCH (NH 2)} CH 3 and the like.

A synthetic route from the compound of the formula (3) to the compound of the formula (I) is shown below by way of example.

Embedded image

By oxidizing the compound of the formula (3) with an oxidizing agent such as PCC (pyridinium chlorochromate), only the compound of the formula (II) can be obtained alone. BH
Reduction of the compound of formula (II) with a reducing agent such as ₃ gives a mixture of compounds of formula (III) and formula (IV). However, the compound of the formula (IV) is converted to the compound of the formula (III) by inversion using methanesulfonyl chloride or the like. Then, using a base such as NaH, the compound represented by the formula (II)
Transesterification is applied to the compound of formula (I) to obtain a compound of formula (V)
Is obtained. The ring expansion reaction by transesterification of the compound of formula (III) is novel. The compound of formula (VI) is obtained by reacting the compound of formula (V) with a nucleophile. formula
Protecting group from the compound of (VI) desorbed by introducing Me group to an amino group, the formula (I) (wherein be ^{R 1 = R 2 = OH;} R 3
= H; R ⁴ is

Embedded image Z ¹ is H; Z ² is Me).

Examples of the oxidizing agent include PCC, PD
C, ozone, sodium periodate, potassium permanganate, ruthenium oxide and osmium tetroxide can be mentioned. More preferably, PCC, PDC, ozone,
Most preferably, it is PCC.

Examples of the above reducing agents include BH ₃ , NaB
_{H 4, LiBH 4, NaBH 3} CN, LiAlH 4, LiAlH
(OtBu) ₃ , Zn (BH ₄ ) ₂ , L-Selectride, LiAl (O
Me) ₃ , diisobutylaluminum hydride and the like. More preferably, BH ₃ , NaBH ₄ ,
LiBH ₄ , NaBH ₃ CN, most preferably BH ₃ .

Examples of the above bases include NaH, NaN
(SiMe ₃ ) ₂ , LiN (SiMe ₃ ) ₂ , KOBu ⁺ , KN (SiM ₃ )
e ₃ ) ₂ , LiOMe, LDA, NaOMe, NaOEt and the like. More preferably, NaH, NaN (S
iMe ₃ ) ₂ , LiN (SiMe ₃ ) ₂ , LDA, most preferably
NaH.

Examples of the above nucleophiles include 1,4-bis
(Bromomagnesio) butane, 1,4-bis (chloromagnesio) butane, 1,4-bis (iodomagnesio) butane,
1,5-bis (bromomagnesio) pentane, 1,5-bis
(Chloromagnesio) pentane, 1,5-bis (iodomagnesio) pentane, or the following halomagnesium, sodium, lithium or potassium salt: 3
-Bromomagnesio-n-propoxide, 3-chloromagnesio-n-propoxide, 3-iodomagnesio-
Examples thereof include n-propoxide, 4-bromomagnesio-n-butoxide, 4-chloromagnesio-n-butoxide, and 4-iodomagnesio-n-butoxide.

More preferably, 1,4-bis (bromomagnesio) butane, 1,4-bis (chloromagnesio) butane, 1,4-bis (iodomagnesio) butane, or
The following halomagnesium, sodium, lithium or potassium salts: 3-bromomagnesio-n-propoxide, 3-chloromagnesio-n-propoxide,
3-iodomagnesio-n-propoxide.

Most preferred are 1,4-bis (bromomagnesio) butane, 1,4-bis (chloromagnesio) butane, and 1,4-bis (iodomagnesio) butane.

The ring expansion reaction of the compound of the formula (III) by transesterification is carried out, for example, by dissolving the compound (III) in a solvent such as tetrahydrofuran (THF) under a nitrogen atmosphere, and cooling the mixture with a base such as sodium hydride. And react. The reaction solution is neutralized by adding an acid, and extracted with an appropriate solvent to obtain a compound of the formula (V).

The 8a-oxahomoerythromycin derivative of the present invention can be formulated as an antibiotic preparation in the same manner as known macrolide antibiotics.

The 8a-oxahomoerythromycin derivative of the present invention may be used in an oral or parenteral pharmaceutical composition such as a tablet, capsule, powder, granule, liquid or suspension,
It can be formulated as sublingual or buccal administration, subcutaneous, intramuscular or intravascular administration and rectal administration. In addition, as an external preparation for purulent diseases used in surgery, ophthalmology, dermatology, etc., ointments, creams, external powders,
It can be prescribed as a spray or the like. These formulations can be made by techniques commonly used by those skilled in the art.

To obtain the desired effect, the dosage should be about 1
It can vary between 00 and about 3000 mg / day. The specific dosage is determined by the attending physician according to the patient's medical history, disease, severity, and other symptoms.

[0038]

EXAMPLES Example 1 Preparation of compound (2) (where Z ¹ = Z ² = benzyloxycarbonyl)

Embedded image

Compound (1) (18.0 g) is mixed with 18 ml of 1,4-dioxane, and 30.6 g of sodium hydrogen carbonate is added to form a slurry. This is heated to 75 ° C., 41.4 g of benzyloxycarbonyl chloride is added dropwise, and the mixture is stirred at the same temperature for 3 hours. After completion of the reaction, the reaction solution was returned to room temperature, and 0.68 ml of triethylamine was added.
Stir for 1 hour. Thereafter, the reaction mixture was filtered, and the residue was washed with a mixture of chloroform and hexane (1: 1).
Concentrate the filtrate and washings. The concentrated residue is removed under reduced pressure
Heat to ° C. and distill off the benzyl alcohol. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1).
6 g (85% yield) of compound (2) are obtained as a colorless foam.

MS (FAB) m / z 995 (M) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.38, 3.02 (two
s, 3H, 3 "-OMe), 2.85, 2.81 (two s, 3H, 3 '
-NMe)

Example 2 Preparation of compound (3) (where Z ¹ = Z ² = benzyloxycarbonyl)

Embedded image

Compound (2) (18 g) was dissolved in 180 ml of tetrahydrofuran, and 5.0 g of potassium carbonate and 4.4 g of carbonyldiimidazole were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution is filtered and concentrated, and the concentrated residue is dissolved in ethyl acetate. The solution was washed twice with water, once with brine, dried over anhydrous sodium sulfate and concentrated.
0.5 g of residue is obtained. This residue and 3.74 ml of benzyl alcohol are dissolved in 180 ml of tetrahydrofuran, 940 mg of sodium hydride (60% oil) is added little by little, and the mixture is stirred at room temperature for 1 hour. After the reaction is completed,
An ice-cooled 10% aqueous phosphoric acid solution is added, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a 10% aqueous phosphoric acid solution, a 5% aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 5:
1 → 4: 1 → 2: 1) to give 16.45 g (yield 81
%) Of compound (3) as a colorless foam.

MS (FAB) m / z 1129 (M) ¹ H-NMR (300 MHz, CDCl ₃ ): δ3.36, 2.94 (two
s, 3H, 3 "-OMe), 2.83, 2.79 (two s, 3H, 3 '
-NMe)

Example 3 Compound (4) by oxidation of compound (3) (where Z ¹ = Z ² =
Preparation of benzyloxycarbonyl) See Reaction Formula C

Embedded image

PCC (pyridinium chlorochromate)
47.8 g (98%) and 57 g of Celite are mixed well and suspended in 350 ml of dichloroethane. In addition, the compound
(3) A solution of (24.38 g) in dichloroethane is added dropwise, and the mixture is stirred at 50 to 55 ° C. for 8 hours. Dilute the reaction mixture with ethyl acetate and filter through celite. The filtrate was concentrated, purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and crystallized from methanol.
6 g (42% yield) of compound (4) are obtained as white crystals.

Mp 170-171 ° C. (MeOH) MS (FAB) m / z 1184 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.37, 2.96 (two
s, 3H, 3 "-OMe), 2.84, 2.79 (two s, 3H, 3 '
-NMe)

Example 4 Compounds (5) and (6) by reduction of compound (4) (wherein
Production of Z ¹ = Z ² = benzyloxycarbonyl) See Reaction Formula B

Embedded image

Compound (4) (10.6 g) was dissolved in 100 ml of tetrahydrofuran, 91.3 ml of a 1.0 M solution of borane in tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction solution was diluted with 250 ml of ethyl acetate, 250 ml of a 5% aqueous sodium hydrogen carbonate solution was added dropwise, and the mixture was stirred under ice cooling for 30 minutes.
This is further diluted with ethyl acetate and an aqueous solution of sodium hydrogen carbonate, and separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel column chromatography using a rover column.
(Hexane: ethyl acetate = 3: 2).
2 g of compound (5) (31% yield) and 6.82 g of compound
(6) (yield 64%) are each obtained as white crystals.

Compound (5): mp 133-134 ° C. (n-hexa
ne, EtOAc) MS (FAB) m / z 1186 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.39, 2.86 (two
s, 3H, 3 "-OMe), 2.81, 2.76 (two s, 3H, 3 '
-NMe)

Compound (6): mp 201-203 ° C. (n-hexa
ne, EtOAc) MS (FAB) m / z 1186 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.38, 2.87 (two
s, 3H, 3 "-OMe), 2.83, 2.78 (two s, 3H, 3 '
-NMe)

Example 5 Preparation of Compound (7) (Z ¹ = Z ² = benzyloxycarbonyl) by Ring Expansion of Compound (6) See Reaction Schemes A and C

Embedded image Compound (6) (2.0 g) was dissolved in 20 ml of tetrahydrofuran under a nitrogen atmosphere and cooled in an ice bath. To this, 103 mg of sodium hydride (60% oil) was added, and under ice cooling,
Stir for 2 hours. After neutralizing the reaction solution by adding 10% hydrochloric acid,
Extract with ethyl acetate. The extract was washed with dilute hydrochloric acid, a 5% sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated and dried under reduced pressure to obtain 2.14 g of a crude product. By silica gel chromatography purification, 1.78 g (yield: 89%) of compound (7) as a white solid is obtained.

MS (FAB) m / z 1186 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.38, 2.98 (two
s, 3H, 3 "-OMe), 2.83, 2.80 (two s, 3H, 3 '
-NMe)

Example 6 Conversion of Compound (5) to Compound (6) (where Z ¹ = Z ² = benzyloxycarbonyl) See Reaction Scheme B

Embedded image

Compound (5) (2.0 g) was dissolved in 20 ml of dichloromethane under a nitrogen atmosphere, and cooled to -40 ° C. in a dry ice-acetone bath. 2.4m of triethylamine
l, 1.3 ml of methanesulfonyl chloride,
Stir for 1 hour and 50 minutes. Ethyl acetate and water are added to the reaction solution, and the mixture is extracted with ethyl acetate. The obtained organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, concentration and drying under reduced pressure, the mesylated product 2.4
8 g are obtained. 2.48 g of the mesylated product is dissolved in 100 ml of tetrahydrofuran-water (4: 1) and stirred in a 75 ° C. oil bath for 2 hours and 40 minutes. After confirming the disappearance of the mesylate by TLC, the reaction solution is concentrated and extracted with ethyl acetate. The obtained organic layer is washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, concentration and drying under reduced pressure, 2.3 g of a crude product is obtained. By silica gel chromatography purification, 1.46 g of compound (6) as a white foamy solid (yield 73)
%).

Example 7 Preparation of compound (8) (where Z ¹ = Z ² = benzyloxycarbonyl) by decyclic carbonate of compound (7)

Embedded image

Compound (7) (100 mg) was added under a nitrogen atmosphere.
It was dissolved in 1 ml of tetrahydrofuran and cooled to -78 ° C in a dry ice-acetone bath. Here, 1,
1,4-prepared from 4-dibromobutane and magnesium
975 μl of a bis (bromomagnesio) butane solution in tetrahydrofuran (0.44 M) is slowly added dropwise, and the mixture is stirred at −78 ° C. for 2 hours and 50 minutes. Confirm the disappearance of raw materials by TLC,
Add 10% hydrochloric acid and ethyl acetate and stir in an ice bath for 20 minutes. The reaction solution is extracted with ethyl acetate, and the organic layer is washed with a 5% aqueous sodium hydrogen carbonate solution, water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, concentration and drying under reduced pressure, 120 mg of a crude product is obtained. By silica gel chromatography purification, 64 mg of compound (8) as a white solid (yield 65
%).

MS (FAB) m / z 1160 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.37, 2.95 (two
s, 3H, 3 "-OMe), 2.83, 2.79 (two s, 3H, 3 '
-NMe)

Example 8 Preparation of compound (9) by deprotecting group of compound (7) (where Z ¹ = Z ² = benzyloxycarbonyl)

Embedded image

Compound (7) (2.00 g) was dissolved in a mixture of 36 ml of 0.5 M acetate buffer (pH 4.5) and 180 ml of ethanol, and palladium hydroxide (20% on carbon) was added thereto.
Add 400 mg and stir at room temperature under a hydrogen atmosphere for 1.5 hours. Then, 13m of 37% formaldehyde aqueous solution
and further stirred under a hydrogen atmosphere at room temperature for 50 minutes. After completion of the reaction, the reaction solution is filtered and concentrated. This is diluted with water, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate,
Concentrate, dissolve the residue obtained in acetone and concentrate again. The obtained residue is dissolved in acetone (5 ml), and water (7.5 ml) is slowly added dropwise thereto slowly, followed by stirring at room temperature for 20 to 30 minutes. After the crystals are precipitated, the crystals are left in a refrigerator for 3 days, and the crystals are collected by filtration. The obtained crystals are washed with a mixture of acetone and water (1: 2) to obtain 1.25 g of compound (9) (yield 94%) as white crystals.

Mp 207-208 ° C. (H ₂ O, acetone) MS (FAB) m / z 776 (M + H) ¹ H-NMR (600 MHz, CDCl ₃ ): δ (ppm) 5.29 (sextet,
1H, J = 5.8 Hz), 5.02 (dd, 1H, J = 9.3H)
z, 3.3 Hz), 4.89 (d, 1H, J = 4.2 Hz), 4.
82 (d, 1H, J = 7.2 Hz), 4.48 (d, 1H, J =
7.8 Hz), 4.31 (t, 1H, J = 4.2 Hz), 4.04
(dq, 1H, J = 9.0 Hz, 6.0 Hz), 3.68 (d, 1
H, J = 6.0 Hz), 3.56 (ddq, 1H, J = 10.8 H
z, 1.4 Hz, 6.0 Hz), 3.31 (s, 3H), 3.26
(dd, 1H, J = 10.5 Hz, 7.5 Hz), 3.04 (d,
1H, J = 9.0 Hz), 2.71 (quintet, 1H, J = 6.
6 Hz), 2.67 (qd, 1H, J = 6.9 Hz, 4.5 Hz),
2.50 (ddd, 1H, J = 12.0 Hz, 10.2 Hz, 3.
6 Hz), 2.35 (d, 1H, J = 15.0 Hz), 2.29
(s, 6H), 1.88 (m, 1H), 1.81 (m, 1H), 1.7
7 (dd, 1H, J = 14.7 Hz, 5.7 Hz), 1.72-
1.66 (m, 3H), 1.65 (m, 1H), 1.59 (dd,
1H, J = 15.0 Hz, 4.8 Hz), 1.48 (s, 3H),
1.36 (d, 3H, J = 6.6 Hz), 1.32 (d, 3H, J
= 7.2 Hz), 1.30 (s, 3H), 1.29 (d, 3H, J
= 6.6 Hz), 1.25-1.23 (two d and s, 9H),
1.10 (d, 3H, J = 7.2 Hz), 0.93 (t, 3H, J
= 7.5 Hz). IR n _max (CHCl ₃ ) 3430, 2970, 2932, 1
801, 1732, 1456, 1378, 1318 cm
^-1

Example 9 Preparation of compound (10) by deprotection of compound (8) (wherein, Z ¹ = Z ² = benzyloxycarbonyl)

Embedded image

Compound (8) (100 mg) was dissolved in a mixture of 1.75 ml of 0.5 M acetate buffer (pH 4.5) and 8.8 ml of ethanol, and palladium hydroxide (20% on carboxyl) was added thereto.
bon), and stirred at room temperature under a hydrogen atmosphere for 1 hour. Thereafter, a 0.6% aqueous 37% formaldehyde solution was used.
Then, the mixture was further stirred under a hydrogen atmosphere at room temperature for 1.5 hours. After completion of the reaction, the reaction solution is filtered and concentrated. This is diluted with water, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration, the resulting residue is purified by rover column chromatography (toluene: chloroform: triethylamine = 5: 4: 1) to obtain compound (10) as a colorless foam. Dissolve this in benzene, freeze-dry and
3 mg (97% yield) of a white powder are obtained.

MS (FAB) m / z 750 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.27 (m, 1H), 4.
91 (d, 1H, J = 4.5 Hz), 4.80 (dd, 1H, J =
9.8 Hz, 2.6 Hz), 4.42 (d, 1H, J = 7.2H
z), 4.27 (dd, 1H, J = 6.6 Hz, 3 Hz), 4.02
(m, 1H), 3.85 (bs, 1H), 3.51 (d, 1H, J =
7.5 Hz), 3.49 (m, 1H), 3.33 (s, 3H), 3.
23 (dd, 1H, J = 9.9 Hz, 7.2 Hz), 3.04
(d, 1H, J = 9.0 Hz), 2.82-2.66 (m, 2H),
2.49 (m, 1H), 2.35 (d, 1H, J = 12 Hz),
2.33 (s, 6H), 2.0-1.8 (m, 3H), 1.7-1.
5 (m, 5H), 1.42 (s, 3H), 1.30 (d, 3H, J
= 6.3 Hz), 1.24-1.20 (four d and s, 15
H), 1.15 (s, 3H), 1.08 (d, 3H, J = 7.5 H
z), 0.91 (t, 3H, J = 7.4 Hz) IR n _max (CHCl ₃ ) 3532, 3438, 2968, 2
932, 1718, 1454, 1378, 1325 cm
^-1

Example 10 Preparation of Compound (12) from Compound (7) (wherein Z ¹ = Z ² = benzyloxycarbonyl)

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A. Compound (7) (400 mg) is dissolved in dichloromethane (5 ml), trichloroacetyl isocyanate (0.2 ml, 5 equivalents of compound (7)) is added, and the mixture is stirred at room temperature under a nitrogen stream for 45 minutes. After adding 3 ml of methanol to the reaction solution and concentrating, a mixed solvent of methanol-water-triethylamine (10 ml-1 ml-0.5 ml) is added, and the mixture is heated under reflux in an oil bath at 85 ° C. for 45 minutes. After returning to room temperature and concentrating to remove methanol, a 5% aqueous sodium hydrogen carbonate solution is added. Extract with ethyl acetate, wash the organic layer with saturated aqueous ammonium chloride solution and dry over anhydrous magnesium sulfate. After filtration and concentration, the obtained residue was purified by rover column chromatography (hexane: ethyl acetate = 1: 1) to obtain 327 mg (yield 79).
%) Of the compound (11).

MS (FAB) m / z 1229 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.39, 2.96 (two
s, 3H, 3 "-OMe), 2.83, 2.79 (two s, 3H, 3 '
-NMe)

[0067]

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B. Compound (11) (100 mg) was 0.5M
1.7 ml of acetate buffer (pH 4.5) and 8.5 ml of ethanol
And palladium hydroxide (20% on)
20 mg of carbon), and the mixture is stirred at room temperature under a hydrogen atmosphere for 85 minutes. Thereafter, 0.62 ml of a 37% aqueous formaldehyde solution was added, and the mixture was further added at room temperature under a hydrogen atmosphere.
Stir for a minute. After completion of the reaction, the reaction solution is filtered and concentrated. It is diluted with water, made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
mg of crude product are obtained. Rover column chromatography (toluene: chloroform: triethylamine = 2
5: 70: 5) to give 59 mg (88 yield).
%) Of the compound (12).

MS (FAB) m / z 819 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.40 (sextet-like,
1H), 5.00 (dd, 1H, J = 3.3 Hz, 9.0 Hz),
4.90 (d, 1H, J = 3.9 Hz) 4.73 (bs, 1H), 4.58 (d, 1H, J = 3.3 Hz),
4.53 (d, 1H, J = 7.5 Hz), 4.23 (dd, 1H,
J = 2.1 Hz, 6.3 Hz), 4.09 (d, 1H, J = 5.7
Hz), 4.02 (dq, 1H, J = 6.3 Hz, 9.3 Hz),
3.53 (m, 1H), 3.33 (s, 3H), 3.20 (dd, 1H)
H, J = 7.2 Hz, 10.2 Hz), 3.05 (bt, 1H, J =
6.6 Hz), 2.81 (quintet, 1H, J = 6.9 Hz),
2.67 (qd, 1H, J = 6.9 Hz, 3.3 Hz), 2.48
(bt-like, 1H), 2.31 (d, 1H, J = 14.4 Hz),
2.32 (s, 6H), 2.24-2.14 (m, 1H), 2.1
3-2.00 (m, 1H), 1.98-1.76 (m, 4H), 1.
73 (s, 3H), 1.70-1.52 (m, 3H), 1.46
(s, 3H), 1.35 (d, 3H, J = 6.3 Hz), 1.31
(d, 3H, J = 6.9 Hz), 1.29-1.19 (m, 12
H), 1.13 (d, 3H, J = 7.5 Hz), 0.92 (t, 3
(H, J = 7.5 Hz)

Example 11 Preparation of compound (13) (wherein, Z ¹ = Z ² = benzyloxycarbonyl)

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Compound (11) (273 mg) was dissolved in tetrahydrofuran (1.9 ml), concentrated hydrochloric acid (1.9 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture is neutralized with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate,
Filtration and concentration gives 262 mg of crude product. Rover column chromatography (hexane: ethyl acetate =
1: 1) to give 162 mg (yield 78%) of compound (13).

MS (FAB) m / z 937 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.84, 2.80 (two
s, 3H, 3'-NMe)

Example 12 Preparation of compound (15) (where Z ¹ = Z ² = benzyloxycarbonyl)

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A. 2 ml of methylene chloride was added under nitrogen to -78
Cool to ℃ and add 36 μl of dimethylsulfoxide and 36 μl of trifluoroacetic anhydride. Compound (13) (11
A solution of 7 mg) in 2 ml of dichloromethane is added via syringe and stirred at -78 ° C for 45 minutes. After monitoring the reaction by TLC, add 89 μl of triethylamine and stir for 20 minutes. After completion of the reaction, neutralize with aqueous sodium hydrogen carbonate solution,
Extract with ethyl acetate. The organic layer is washed with water and saline,
After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated to 113 m
g of crude product are obtained. Purification was performed by rover column chromatography (hexane: ethyl acetate = 1: 1),
76 mg (yield 65%) of compound (14) is obtained.

The asymmetric carbon at the 2-position of the present compound (14) is
Although it is not epimerized immediately after the reaction, it has been revealed that epimerization easily occurs in the presence of methanol or an organic base, and that the configuration at the 2-position is completely scrambled during the chromatographic purification process.

MS (FAB) m / z 913 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.84, 2.81 (two
s, 3H, 3'-NMe)

[0077]

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B. Compound (14) (76 mg) was dissolved in a mixture of 1.7 ml of 0.5 M acetate buffer (pH 4.5) and 8.3 ml of ethanol, and palladium hydroxide (20% on carboxyl) was added thereto.
bon) 15 mg and added at room temperature under a hydrogen atmosphere for 2 hours 40
Stir for a minute. Thereafter, 0.63 ml of a 37% aqueous formaldehyde solution was added, and the mixture was further added at room temperature under a hydrogen atmosphere at 40
Stir for a minute. After completion of the reaction, the reaction solution is filtered and concentrated. It is diluted with water, neutralized with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
mg of crude product are obtained. Rover column chromatography (toluene: chloroform: triethylamine = 2
5: 70: 5) to give 38 mg (yield 69).
%) Of compound (15).

MS (FAB) m / z 659 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.36-5.22 (m, 2
H), 5.12-5.00 (m, 2H), 4.93-4.99 (m, 1
H), 4.86-4.80 (d, 1H, J = 4.5 Hz), 4.7
0 (d, 1H, J = 4.2 Hz), 4.63 (d, 1H, J =
3.0 Hz), 4.54-4.45 (quartet-like, 1H), 4.
39 (d, 1H, J = 7.2 Hz), 3.91-3.78 (quin
tet-like, 2H), 3.68-3.40 (m, 4H), 3.38-
3.26 (bs, 1H), 3.26-3.16 (m, 2H), 3.1
5-3.02 (m, 1H), 2.86-2.66 (m, 2H), 2.
58-2.44 (m, 2H), 2.29, 2.27 (two s, 1
2H), 2.25-2.00 (m, 4H), 1.98-1.75
(m, 2H), 1.75-1.55 (m, 6H), 1.65, 1.6
4 (two s, 6H), 1.51, 1.50 (two s, 6H), 1.
44 (d, 3H, J = 7.2 Hz), 1.40 (d, 3H, J =
7.5 Hz), 1.36-1.18 (m, 24H), 1.00 (t,
3H, J = 7.5 Hz), 0.94 (t, 3H, J = 7.5H
z)

Example 13 Preparation of Compounds (19a) and (19b) from Compound (7) Formula (I) (where Z ¹ = Z ² = benzyloxycarbonyl)

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A. Compound (7) (3.00 g) was added to DMF30.
of sodium hydride (60% in o.
il) Add 206 mg and stir at 60 ° C. for 22 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate and washed once with a 10% aqueous phosphoric acid solution, once with a 5% aqueous sodium hydrogen carbonate solution and twice with a saline solution. The extract was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was subjected to silica gel column chromatography using a rover column (hexane: ethyl acetate = 2:
Purification in 1) gives 2.43 g (84% yield) of compound (16) as a colorless foam.

MS (FAB) m / z 1142 (M + Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.37, 2.97 (two
s, 3H, 3 "-OMe), 2.83, 2.80 (two s, 3H,
3'-NMe)

[0083]

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B. Compound (16) (247 mg) is dissolved in 2 ml of tetrahydrofuran and cooled to -40 ° C. In addition, 1.0% of sodium bis (trimethylsilyl) amide
M tetrahydrofuran solution (0.22 ml) was added, and -40 was added.
Stir at 10 ° C. for 10-15 minutes. A solution of 143 mg of carbonyldiimidazole in a mixture of dimethylformamide and tetrahydrofuran (2: 3) was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is ice-cooled, a 0.5 M aqueous solution of sodium dihydrogen phosphate is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with brine three times, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 202 mg (75% yield).
To give compound (17) as a colorless foam.

MS (FAB) m / z 1214 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.33, 2.93 (two
s, 3H, 3 "-OMe), 2.83, 2.79 (two s, 3H,
3'-NMe)

[0086]

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C. Compound (17) (1.50 g) was suspended in a mixture of 1.5 ml of acetonitrile and 13.5 ml of water, and 1.00 ml of 4-phenylbutylamine (98%) was added thereto, followed by stirring at 35 ° C. for 5 hours. I do. The reaction solution is returned to room temperature, diluted with ethyl acetate, washed twice with a 0.5 M aqueous solution of sodium dihydrogen phosphate, once with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue is subjected to silica gel chromatography (hexane: ethyl acetate = 3: 1).
→ 2: 1) to give 1.52 g (95% yield) of a mixture of compound (18) and compound (19) as a colorless foam.

[0088]

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D. Mixture of compound (18) and compound (19)
(1.50 g) in 30 ml of tetrahydrofuran,
Cool to -78 ° C. To this was added a 1.0 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran.
Add 2 ml and stir at the same temperature for 1 hour. After completion of the reaction, a 0.5 M aqueous solution of sodium dihydrogen phosphate is added, and the mixture is extracted with ethyl acetate. After liquid separation, the organic layer is washed once with water and brine once, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by silica gel column chromatography using a rover column (benzene: isopropyl ether = 1: 2 → benzene: isopropyl ether: ethyl acetate = 1: 2: 1) to obtain 1.04 g of the compound ( 19a) (66% yield) and 234 mg of compound (19
b) (15% yield) are each obtained as colorless foams.

Compound (19a): MS (FAB) m / z 1317 (M
+ Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.35, 3.01 (two
s, 3H, 3 "-OMe), 2.83, 2.79 (two s, 3H,
3'-NMe)

Compound (19b): MS (FAB) m / z 1317 (M
+ Na) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.40, 2.96 (two
s, 3H, 3 "-OMe), 2.85, 2.81 (two s, 3H,
3'-NMe)

Example 14 Preparation of Compound (20) from Compound (19a) (wherein Z ¹ = Z ² = benzyloxycarbonyl)

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Compound (19a) (700 mg) was dissolved in a mixture of 11 ml of 0.5 M acetate buffer (pH 4.5) and 55 ml of ethanol, and palladium hydroxide (20% on carbohydrate) was added thereto.
n) 140 mg was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Then, a 37% aqueous formaldehyde solution 4.1
Then, the mixture is further stirred under a hydrogen atmosphere at room temperature for 1 hour. After completion of the reaction, the reaction solution is filtered and concentrated. This is diluted with water, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (toluene: chloroform: triethylamine = 70: 25: 5),
452 mg of a brown foam are obtained. This is crystallized from ethyl acetate to obtain 308 mg of compound (20) (63% yield) as white crystals.

MS (FAB) m / z 907 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ7.29-7.25 (m, 2
H), 7.20-7.12 (m, 3H), 5.43 (dd, 1H, J =
9.3 Hz, 6.6 Hz), 4.94 (dd, 1H, J = 9.2
Hz, 3.5 Hz), 4.78 (d, 1H, J = 3.9 Hz), 4.
38 (d, 1H, J = 3.9 Hz), 4.37 (d, 1H, J =
7.2 Hz), 4.04 (m, 1H), 3.79 (brs, 1H),
3.66 (dt, 1H, J = 14.4 Hz, 7.5 Hz), 3.5
2-3.42 (m, 3H), 3.30 (s, 3H), 3.26 (d
d, 1H, J = 9.9 Hz, 7.2 Hz), 3.02 (t, 1H,
J = 9.6 Hz), 2.88-2.72 (m, 2H), 2.67-
2.55 (m, 2H), 2.55-2.39 (m, 2H), 2.3
0 (s, 6H), 2.25 (d, 1H, J = 10.5 Hz), 1.
96-1.76 (m, 3H), 1.74-1.46 (m, 9H),
1.44 (s, 3H), 1.30-1.20 (three d's and t
wo s's, 15H), 1.16 (t, 6H, J = 6.5 Hz), 1.
06 (d, 3H, J = 6.6 Hz), 0.94 (t, 3H, J =
7.5 Hz).

Example 15 Preparation of compound (22) from compound (7) (wherein Z ¹ = Z ² = benzyloxycarbonyl)

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A. Compound (7) (5.48 g) was dissolved in 40 ml of tetrahydrofuran and cooled in an ice bath. Concentrated hydrochloric acid 3
8 ml was added, and further 15 ml of tetrahydrofuran was added, followed by stirring at room temperature for 3.5 hours. This is diluted with water, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 4.3 g of compound (21).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.85,
2.81 (two s, 3H, 3'-NMe)

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B. Compound (21) (4.3 g) was added to ethanol 2
Dissolved in 00 ml and 40 ml of 0.2 M acetate buffer,
860m of palladium hydroxide (20% on carbon)
g and stirred at room temperature under a hydrogen atmosphere for 4 hours. Then, 36 ml of 37% aqueous formaldehyde solution was added,
The mixture is further stirred under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction solution is filtered and concentrated. This is diluted with water,
Make alkaline with sodium bicarbonate and extract with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (toluene: chloroform: triethylamine = 70: 25: 5), and 2.15 g (yield: 74% from (7) of a two-step reaction) of a white foam was obtained. Compound (22) is obtained.

MS (FAB) m / z 618 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.23 (dd, 1H, J =
4.2 Hz, 9.0 Hz), 4.83 (d, 1H, J = 2.4H
z), 4.88-4.76 (m, 1H), 4.56 (d, 1H, J =
4.2 Hz), 4.44 (d, 1H, J = 9.9 Hz), 4.3
7 (d, 1H, J = 7.2 Hz), 3.99 (bs, 1H), 3.
93 (dd, 1H, J = 3.9 Hz, 10.5 Hz), 3.90
(d, 1H, J = 2.4 Hz), 3.74-3.60 (m, 1H),
3.31 (dd, 1H, J = 10.5 Hz, 7.5 Hz), 2.7
4 (dq, 1H, J = 9.9 Hz, 6.6 Hz), 2.65-2.
46 (m, 2H), 2.28 (s, 6H), 1.92 (dd, 1H,
J = 10.8 Hz, 14.4 Hz), 1.82-1.64 (m, 4
H), 1.49 (d, 3H, J = 5.7 Hz), 1.5-1.3
(m, 2H), 1.40 (d, 3H, J = 6.9 Hz), 1.33
(d, 3H, J = 6.9 Hz), 1.28 (d, 3H, J = 6.0
Hz), 1.27 (s, 3H), 1.24 (s, 3H), 0.98-
0.89 (m, 6H)

Example 16 Preparation of compound (25) (where Ac = acetyl)

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A. Compound (22) (1.0 g) was dissolved in 40 ml of a mixed solvent of dichloromethane: acetone = 1: 1,
Under ice cooling, 0.22 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution is concentrated and neutralized by adding a 5% aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain 1.08 g of a white foamy compound (23) as a crude product.

MS (FAB) m / z 660 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.20 (dd, 1H, J =
4.8 Hz, 8.1 Hz), 4.96-4.83 (m, 1H), 4.
79 (dd, 1H, J = 7.8 Hz, 10.5 Hz), 4.58
(d, 1H, J = 9.0 Hz), 4.55 (d, 1H, J = 7.8
Hz), 4.37 (bs, 1H), 3.95 (d, 1H, J = 9.6
Hz), 3.91 (d, 1H, J = 2.1 Hz), 3.72-3.5
8 (m, 1H), 2.80 (ddd, 1H, J = 12.3 Hz, 1
0.8 Hz, 4.2 Hz), 2.72 (qd, 1H, J = 6.1H
z, J = 15.3 Hz), 2.58 (qd, 1H, J = 7.2H
z, J = 9.0 Hz), 2.25 (s, 6H), 2.11 (s, 3
H), 1.93-1.54 (m, 6H), 1.44 (d, 3H, J =
6.0 Hz), 1.38 (d, 3H, J = 6.9 Hz), 1.3
3 (d, 3H, J = 6.9 Hz), 1.29 (s, 3H), 1.3
1-1.24 (d, 3H), 1.20 (s, 3H), 1.5-1.1
8 (m, 1H), 0.94 (t, 3H, J = 7.5 Hz), 0.8
7 (d, 3H, J = 7.2 Hz)

[0103]

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B. Add DMF (0.125 ml) to p-nitrophenylacetic acid (2.93 g) and thionyl chloride (1.5 ml) and heat in an oil bath at 80 ° C. for 15 minutes. Return to room temperature,
30 ml of benzene is added, and the mixture is concentrated under reduced pressure to remove excess thionyl chloride. The concentrated residue is dissolved in dichloromethane (40 ml) and cooled with ice. Compound (23) (1.08 g) and pyridine
(1.31ml) dissolved in dichloromethane 20m
1 is separately adjusted, put into a dropping funnel, and slowly dropped into the reaction solution. The dropping funnel is dichloromethane 2
Wash with 0 ml, and add the washing solution to the reaction solution. The mixture was stirred under ice cooling for 5.5 hours, and further stirred at room temperature for 1 hour and 20 minutes. Neutralize by adding 5% aqueous sodium bicarbonate. After extraction with ethyl acetate, the organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue is purified by silica gel column chromatography using a rover column (toluene: chloroform: triethylamine = 75: 20: 5 → 25: 70: 5) to obtain 789 mg (yield 59%) of compound (24). .

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.22
(d, 2H, J = 8.7 Hz), 7.52 (d, 2H, J = 9.0
Hz), 5.42 (dd, 1H, J = 7.5 Hz, 3.0 Hz),
5.21 (m, 1H), 5.07 (d, 1H, J = 5.1 Hz),
4.99 (dd, 1H, J = 4.2 Hz, 8.4 Hz), 4.76
(dd, 1H, J = 10.8 Hz, 7.5 Hz), 4.16 (d,
1H, J = 7.5 Hz), 3.82 (s, 2H), 3.53 (d,
1H, J = 4.5 Hz), 3.30 (m, 1H), 2.87 (bs,
1H), 2.76-1.52 (m, 3H), 2.25 (s, 6H),
2.2-2.1 (m, 1H), 2.08 (s, 3H), 1.9-1.5
6 (m, 6H), 1.43 (s, 3H), 1.30 (two d, 6H)
H), 1.20 (s, 3H), 1.19 (d, 3H, J = 6.3 H
z), 1.05 (d, 3H, J = 7.2 Hz), 0.97 (t, 3
H, J = 7.5 Hz), 0.92 (d, 3H, J = 7.2 Hz)

[0106]

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C. Compound (24) (779 mg) is dissolved in 2 ml of methanol, and the mixture is heated under reflux on a 70 ° C. oil bath. After 1 hour, return to room temperature and concentrate. The residue was subjected to silica gel column chromatography using a rover column (toluene:
Purification with chloroflume: triethylamine = 70: 25: 5) gives compound (25) (583 mg). Yield 79
%.

MS (FAB) m / z 781 (M + H) ¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.19 (d, 2H, J =
9.0 Hz), 7.51 (d, 2H, J = 8.7 Hz), 5.48
(dd, 1H, J = 1.8 Hz, 8.1 Hz), 5.20 (sexte
t, 1H, J = 5.4 Hz), 5.05 (dd, 1H, J = 3.9)
Hz, 8.7 Hz), 4.93 (d, 1H, J = 6.6 Hz), 4.
15 (d, 1H, J = 7.5 Hz), 3.82 (s, 2H), 3.
69 (d, 1H, J = 3.6 Hz), 3.55 (bs, 1H), 3.
5-3.35 (m, 2H), 3.22 (dd, 1H, J = 7.2H
z, 10.2 Hz), 2.78-2.62 (m, 2H), 2.37
(ddd, 1H, J = 12.3 Hz, 10.2 Hz, 3.9 Hz),
2.26 (s, 6H), 2.06-1.92 (m, 1H), 1.8
4-1.58 (m, 6H), 1.39 (s, 3H), 1.37 (d,
3H, J = 6.3 Hz), 1.33 (d, 3H, J = 7.2H
z), 1.23 (s, 3H), 1.21 (d, 3H, J = 6.3 H
z), 1.08 (d, 3H, J = 7.2 Hz), 1.01 (d, 3
H, J = 6.9 Hz), 0.94 (t, 3H, J = 7.2 Hz)

Measurement of antibacterial activity The minimum inhibitory concentration (M) was determined for compound (10) of Example 9.
(IC: μg / ml) was measured by the agar plate dilution method based on the standard method of the Japanese Society of Chemotherapy. However, a susceptible disk medium was used as a medium, and one loopful of about 10 ⁶ cfu / ml was inoculated.

[0110]

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MIC (μg / ml) Staphylococcus aureus 209P JC-1 0.78 Staphylococcus aureus SMITH 1.56 Streptococcus pyogenes O-203 0.39 Streptococcus nidumonier Type III 0.2 Streptococcus nidumonier SR16675・ Fesium SR4512 6.25 Haemophilus influenza 88562 3.13 Blanchamera catarralis SR11341 0.2

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C057 KK11 4C086 AA01 AA02 AA03 AA04 EA12 MA01 MA04 NA14 ZB35

Claims (9)

[Claims] 1. A compound of the formula (I): (Wherein R ¹ ＲR ²ま た は OH or R ¹ and R ² together form (Where R ⁵ = (CH ₂ ) n-aryl, and n is 1-6
R ³ ＨH, an acyl group, or an optionally substituted lower alkyl group, or 3
R ⁴ ＨH, an acyl group or Or forms a CＯO with the ring carbon at position 3 (shown in dotted lines); Z ¹ is a protecting group for H or a hydroxy group; Z ² is a protecting group for Me or an amino group is there)
Or a salt, prodrug or hydrate thereof. 2. A compound of formula (I ′): (Wherein R ¹ , R ² , R ³ , R ⁵ , Z ¹ and Z ² are
R ⁴ = H, an acyl group, or Or forms C ＝ O with the ring member carbon at position 3.
(Indicated by a dotted line)), a salt thereof, a prodrug, or a hydrate thereof. 3. Reaction formula A: (Wherein, R ⁶ is H, an acyl group or a sulfonyl group,, Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group),
A method for producing a compound represented by the formula: 4. Reaction formula B: (Wherein, R ⁶ is H, an acyl group or a sulfonyl group,, Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group),
A method for producing the compound represented by I). 5. Reaction formula C: (Wherein, R ⁶ is H, an acyl group or a sulfonyl group,, Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group),
A method for producing a compound represented by the formula: 6. A compound of the formula (II): (Wherein Z ¹ is H or a protecting group for a hydroxy group;
Z ² is a protecting group for Me or an amino group). 7. A compound of the formula (III): (Wherein, R ⁶ is H, an acyl group or a sulfonyl group,; Z ¹ is a protecting group of H or a hydroxyl group; Z ²
Is a protecting group for Me or an amino group). 8. Formula (V): (Wherein Z ¹ is H or a protecting group for a hydroxy group;
Z ² is a protecting group for Me or an amino group). 9. A pharmaceutical composition comprising the 8a-oxahomoerythromycin derivative according to claim 1 or 2.